7. Abstract Magnetic resonance imaging (MRI) is widely used for the diagnosis of advanced osteoarthritis (OA), but is less sensitive for the diagnosis of early OA. There are three major barriers to progress in evaluation of early OA. First, OA is a ?whole organ disease? involving all the principal knee joint tissues. However, many tissues or tissue components such as the deep layers of cartilage, menisci, ligaments, tendons and bone have short T2s and show little or no signal with conventional clinical sequences. Second, distinct proton groups, namely water protons and macromolecular protons are present in most joint tissues. Macromolecular protons in many the knee joint tissues, especially the short T2 tissues have not been investigated with clinical sequences. Third, extensive research over the past two decades has focused on two particular biomarkers for OA: T2 and T1?, with T2 sensitive to collagen degradation, and T1? sensitive to proteoglycan (PG) depletion. The main confounding factor is the magic angle effect, which may result in a several fold increase in T2 and T1? when the tissue fibers are oriented ~54? to the B0 field. This often far exceeds the change produced by disease. We have developed 3D ultrashort echo time (UTE) sequences with TEs as short as 8 s that are 100-1000 times shorter than the TEs of clinical sequences. These allow us to directly image ?MR invisible? joint tissues. Recently adiabatic spin-lock imaging has been proposed to measure T1?. Magnetization transfer (MT) imaging has been introduced to assess macromolecular protons. Most importantly, the adiabatic T1? and MT biomarkers are magic angle insensitive. In this proposal, we will further develop a 3D adiabatic-UTE-T1? sequence for magic angle insensitive T1? measurement, and a UTE-MT sequence for magic angle insensitive biomarkers of MT ratio (MTR) and MT modeling of macromolecular fractions and exchange rates. We will further evaluate the 3D adiabatic-UTE-T1? and UTE-MT techniques for evaluation of macromolecules and water components in both short and long T2 tissues in normal knee joint specimens (Aim 1). We expect that the UTE-adiabatic-T1? biomarker will be sensitive to PG depletion, while the UTE MTR and MT modeling parameters will be sensitive to PG and collagen changes in the knee joint tissues. Then we will compare the novel 3D UTE and clinical sequences for quantitative evaluation of cadaveric human knee specimens with normal (n=20), mild (n=20) and moderate (n=20) OA (Aim 2). We expect that the UTE-adiabatic-T1? and UTE-MT sequences will be more sensitive to degeneration in the principal knee joint tissues than conventional clinical sequences. Finally, we will apply 3D UTE-adiabatic-T1? and UTE-MT techniques to evaluate knee joint degeneration in healthy volunteers (n=20) and patients (n=20) 6 months, 1 year, and 2 years after anterior cruciate ligament (ACL) reconstruction. We will correlate the MR measures with clinical scores (Aim 3). We expect the UTE measures will be more sensitive than clinical MRI measures to changes in the knee of patients after ACL reconstruction. The study is likely to have a major impact on making early OA diagnosis and monitoring disease progression.